PROJECT SUMMARY Inhibition of the renal SGLT2 transporter has proven to be an effective therapeutic intervention to reduce plasma glucose levels and HbA1c in type 2 diabetic patients. The glycemic-lowering efficacy of the SGLT2 inhibitors results from two distinct mechanisms: (i) induction of glucosuria, which amounts to ~70-90 grams per day and (ii) amelioration of glucotoxicity leading to increased insulin sensitivity in muscle and improved beta cell function (JCI 124:509-514, 2014). However, the clinical efficacy of the SGLT2 inhibitors is countered by an increase in endogenous glucose production (EGP) that offsets by ~50% the amount of glucose excreted in the urine. The increase in EGP is associated with a rise in plasma glucagon concentration and decline in plasma insulin concentration. In the present grant we will define: (1) the organ, liver and/or kidney, responsible for the increase in EGP (Protocol One); (2) the role of increased plasma glucagon, decline in plasma insulin, fall in plasma glucose concentration (Protocol Two); and (3) the role of the renal nerves in the increase in EGP (Protocol Three) following inhibition of the renal SGLT2 transporter with dapagliflozin. In Protocol Four, we will examine whether the GLP-1 receptor agonist, exenatide, which stimulates insulin and inhibits glucagon secretion, can block the increase in EGP following SGLT2 inhibition with dapagliflozin.